Cortical Selective Neuronal Loss, Impaired Behavior, and Normal Magnetic Resonance Imaging in a New Rat Model of True Transient Ischemic Attacks

Abstract

M ost transient ischemic attacks (TIAs) are secondary to transient arterial occlusion from upstream blood clot. According to their new tissue-based definition, TIAs are characterized both clinically by focal neurological symptoms of ischemic origin lasting <24 hours and radiologically by a lack of topographically congruent changes on diffusion-weighted imaging (DWI) or FLAIR magnetic resonance imaging (MRI) performed within 2 weeks of the clinical event.1 Normal imaging in true TIAs, which account for 20% to 50% of all clinically diagnosed TIAs, 2 makes them difficult to differentiate from nonischemic transient focal neurological events; hence, their diagnosis rests entirely on clinical skills. Up to 45% of all DWI-negative transient focal neurological events are eventually not classified as genuine TIAs. The lack of detectable changes on structural MRI in TIAs does not, however, rule out the presence of microscopic damage, such as selective neuronal loss (SNL) and microglial activation (MA). Recently, impairment in subtle cognitive tests after TIAs, despite normal neurological examination, has been repeatedly reported, 3-5 suggesting underlying tissue damage. Interestingly, positron emission tomography imaging using appropriate tracers is able to detect SNL and MA in vivo. 6,7 It is therefore of translational importance to develop rodent models of MRI-negative TIAs to investigate whether these histopathologic changes effectively occur and, if so, characterize their behavioral counterparts.Previous work using brief proximal middle cerebral artery occlusion (MCAo) in rats has documented the occurrence of SNL and MA, despite normal MRI. 8,9 However, this model primarily targets the striatum, whereas in the clinical setting, TIAs tend to preferentially affect the cortex.10,11 Furthermore, cortical damage is more likely to result in long-lasting Background and Purpose-New-definition transient ischemic attacks (TIAs) are frequent but difficult to diagnose because magnetic resonance imaging (MRI)-negative by definition. However, hidden underlying cell damage might be present and account for the reported long-lasting cognitive impairment after TIAs. Most prior rodent models of true TIA targeted the striatum or have not been fully characterized. Here we present the MRI, behavioral, and quantitative cell changes characterizing a new rodent model of true TIA targeting the more behaviorally relevant cerebral cortex. Methods-Fifteen-minute distal middle cerebral artery occlusion was performed in 29 spontaneously hypertensive rats allowed to survive for 7 to 60 days. Behavior was assessed serially using both global neurological and fine sensorimotor tests. Diffusion-and T2-weighted MRI was obtained 20 min postreperfusion and again 7 to 60 days later, and then changes in neurons and microglia were quantified across the middle cerebral artery territory using immunohistochemistry. Results-No MRI changes or pan-necrosis were observed at any time point, but patchy cortical selective neuronal loss affected 28/29 rats, regardless...

Molecular magnetic resonance imaging discloses endothelial activation after transient ischaemic attack

“…This observation first suggests that despite no evidence of macroscopic damage, TIA actually induces tissue sequelae, consistent with previous post-mortem histological findings (Ejaz et al, 2015(Ejaz et al, , 2016, but that our MRI modality noninvasively unmasks. Second, in the clinical setting, this time window gives a reasonable opportunity to process imaging, and to identify patients eligible for prevention.…”

“…Here, we first implemented and optimized previous models to establish a preclinical mouse model of TIA complying with the tissue-based definition. This model combines the advantages of these previous models (Fieschi et al, 1975;Arsava et al, 2009;Pedrono et al, 2010;Morancho et al, 2012;Ejaz et al, 2015): it is relatively non-invasive, robust, reproducible, easy to control, and preserves the dura. The main achievement with this model is the supply of an MRI-based objective evidence of TIA.…”

Mapping the dynamics of brain perfusion using functional ultrasound in a rat model of transient middle cerebral artery occlusion

“…44 However, the site of SNL is known to dictate the behavioral effects of stroke, with striatal SNL seemingly having less clear sensorimotor effects than cortical SNL. 16,45 Severe striatal SNL has, however, been reported to impair performance on sophisticated cognitive tests, 46,47 but these were not implemented in the present study.…”

Electroacupunctre improves motor impairment via inhibition of microglia-mediated neuroinflammation in the sensorimotor cortex after ischemic stroke

“…It has been reported that activated microglia increased proinflammatory cytokines, including TNF-α, IL-1β and IL-6 in the ischemic stroke, which exacerbates the cortical selective neuronal loss and long-lasting sensorimotor behavior deficits [7][8]17,[55][56]. Long-term neuroinflammation is strongly induced gray-and white-matter damage, which contributes to long-term sensorimotor impairment [57].…”

“…Simultaneously, the cerebral I/R characterized by microglia-mediated neuroinflammation is involved in the brain edema, blood-brain barrier damage and neuronal loss or degeneration, which cause long-lasting neurological and sensorimotor deficits [17][18]. Therefore, attenuating of neuroinflammation effectively protects brain, which is considered as an important therapeutic strategy for improving neurological function after ischemic stroke [19][20].…”